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Originally published In Press as doi:10.1074/jbc.R500007200 on July 26, 2005

J. Biol. Chem., Vol. 280, Issue 37, 32049-32052, September 16, 2005
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Leukotriene B4 Receptor and the Function of Its Helix 8*

Toshiaki Okuno{ddagger}§1, Takehiko Yokomizo{ddagger}, Tetsuya Hori||, Masashi Miyano||, and Takao Shimizu{ddagger}

From the Department of {ddagger}Biochemistry and Molecular Biology and §Metabolome, Faculty of Medicine, The University of Tokyo, and PRESTO of Japan Science and Technology Agency, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, and ||Structural Biophysics Laboratory, RIKEN Harima Institute at Spring-8, 1-1-1 Kouto, Mikazuki, Sayo-gun, Hyogo 679-5148, Japan


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 Discovery and Signaling of...
 Physiological Roles of BLT1
 Discovery and Signaling of...
 Biochemical Characterization of...
 Conclusion
 REFERENCES
 
More than 30 lipid ligands, which express their biological activities through cognate G-protein-coupled receptors (GPCRs), have been reported. Among them, leukotriene B4 (LTB4) is a potent lipid mediator involved in host defense, inflammation, and the immune responses. Two GPCRs for LTB4 (BLT1 and BLT2) have been cloned and analyzed. Recent studies using genetically engineered mice suggest that BLT1 plays an important role in several inflammatory diseases including ischemic reperfusion tissue injury, atherosclerosis, and bronchial asthma. BLT1 is also a good tool to study the molecular mechanism of GPCR activation and inactivation in vitro. In this brief review, we focus on the biological and biochemical properties of BLT1 with special attention to the putative helix 8 of the receptor.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
Discovery and Signaling of...
 Physiological Roles of BLT1
 Discovery and Signaling of...
 Biochemical Characterization of...
 Conclusion
 REFERENCES
 
Prostaglandins, leukotrienes (LTs),2 platelet-activating factor (PAF), lysophosphatidic acid, sphingosine 1-phosphate, endocannabinoids, and free fatty acids all exert a variety of biological activities through GPCRs (Fig. 1). These mediators are collectively termed lipid mediators. LTB4 (5(S),12(R)-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid) is an extremely potent lipid inflammatory mediator, originally discovered as a chemotactic factor (1, 2). It is biosynthesized from membrane phospholipids by the sequential and concerted action of cytosolic phospholipase A2, 5-lipoxygenase, and LTA4 hydrolase (3–6). Two distinct GPCRs for LTB4, BLT1 and BLT2, have been identified (7, 8). BLT1 is a high affinity specific receptor for LTB4, whereas BLT2 is a low affinity receptor for LTB4 that also binds other eicosanoids. The LTB4-BLT1 axis participates in the recruitment and activation of leukocytes as a part of the immune response against invading pathogens (9) as well as in the pathogenesis of various inflammatory diseases (10).


   Discovery and Signaling of BLT1
TOP
 ABSTRACT
 INTRODUCTION
 Discovery and Signaling of...
Physiological Roles of BLT1
 Discovery and Signaling of...
 Biochemical Characterization of...
 Conclusion
 REFERENCES
 
LTB4 binding sites were detected in membrane fractions of polymorphonuclear leukocytes and macrophages (11–14), and this binding was believed to be mediated by GPCRs for LTB4 (15, 16). A high affinity LTB4 receptor (BLT1) was cloned by Yokomizo et al. (17) from retinoic acid-differentiated HL-60 cells using a cDNA subtraction strategy. Membrane fractions of COS-7 cells transfected with BLT1 showed a high affinity for LTB4 with a Kd value comparable to that observed in differentiated HL-60 cells. BLT1 is expressed exclusively in leukocytes in both human and mouse as revealed by Northern blot analysis, suggesting its tissue- and cell-specific transcriptional regulation. BLT1, expressed in CHO (Chinese hamster ovary) cells, coupled to the Gi and Gq family of G-proteins, inhibited adenylate cyclase and activated phospholipase C, respectively. Notably, CHO cells expressing BLT1 showed robust chemotactic activity toward LTB4, mediated by the Gi family of G-proteins (17). Haribabu et al. (18) reported that both pertussis toxin (PTX)-sensitive and -insensitive G-proteins mediate activation of phospholipase C and enzyme release following exposure to LTB4 in rat basophilic leukemia cells expressing BLT1. However, using the same cells, Ito et al. (19) reported that BLT1-mediated calcium increase, enzyme release, and inositol 1,4,5-trisphosphate production were inhibited by PTX treatment. Although no clear explanation of this discrepancy is available, at least PTX-sensitive G-protein is important for intracellular signaling following BLT1 activation. Detailed analysis of the molecular mechanism for BLT1-dependent activation of different G-proteins requires further study.


   Physiological Roles of BLT1
TOP
 ABSTRACT
 INTRODUCTION
 Discovery and Signaling of...
 Physiological Roles of BLT1
Discovery and Signaling of...
 Biochemical Characterization of...
 Conclusion
 REFERENCES
 
BLT1–/– mice have been established and analyzed by two independent groups. LTB4-induced chemotaxis is abrogated in BLT1–/– neutrophils, and LTB4-induced calcium influx is absent in BLT1–/– neutrophils and peritoneal macrophages (20, 21), clearly showing that BLT1 is a predominant functional LTB4 receptor in these cells. BLT1–/– mice exhibited reduced lethality induced by PAF, showing that LTB4 functions as a downstream effector of PAF in anaphylactic shock. LTB4 is produced more rapidly by serial enzymatic reactions than are peptide chemokines, which require transcription and translation for their biosynthesis. Recent reports showed that the LTB4-BLT1 axis controls the early phase of immunological reactions by activating and recruiting T lymphocytes (22–25). Tager and co-workers (25–27) reported that BLT1 is not expressed in naïve T cells but is induced in Th1- or Th2-skewed CD4+ T cells and mediates early T cell recruitment into the airway in an asthma model. Ott et al. (24) proposed that mast cell-derived LTB4 (upon cross-linking of the Fc{epsilon} receptors) is the initial trigger for migration of CD8+ effector T cells into the inflamed lesion. Previously, Kato et al. (28) showed that methylation at the CpG sites in the BLT1 promoter is related to leukocyte-specific transcription of the BLT1 gene, but the molecular mechanism of induction of BLT1 during Th1 and Th2 differentiation remains unclear. Identification of the cells that produce LTB4, other than mast cells, also is an important issue to be addressed in this asthmatic model. Leukocytes (especially monocytes) invading the arterial intima are critical in the development of atherosclerotic lesions (29). Aiello et al. (30) reported that a BLT1 antagonist, CP-105696, reduced the formation of atherosclerotic plaques in both apoE–/– and LDLR–/– mice. Studies using BLT1-deficient mice on an apoE–/– background also showed the importance of the LTB4-BLT1 interaction in atherogenesis (31). Although much information on the LTB4-BLT1 axis has accumulated using various animal disease models, further study is required for identification of the cells that are affected by BLT1 deficiency (TABLE ONE). The preceding are several key studies that aim to identify the cells that are involved in the mechanism of leukocyte trafficking and transcriptional regulation of BLT1 in differentiated T cells.


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  		TABLE ONE
Physiological and pathophysiological roles of LTB4

Diseases are shown in italics.

 

   Discovery and Signaling of BLT2
TOP
 ABSTRACT
 INTRODUCTION
 Discovery and Signaling of...
 Physiological Roles of BLT1
 Discovery and Signaling of...
Biochemical Characterization of...
 Conclusion
 REFERENCES
 
Binding studies using [3H]LTB4 had suggested the presence of a low affinity LTB4 receptor in addition to a high affinity receptor. BLT2, another G-protein-coupled LTB4 receptor, was independently identified by four groups (32–35). Yokomizo and co-workers (28, 32) identified human BLT2 while analyzing the promoter of BLT1. The human BLT2 gene is located ~3 kb upstream of the human BLT1 open reading frame, and the primary structure of BLT2 is most similar to BLT1 (45% amino acid identity, Fig. 1) among the superfamily of GPCRs (28). BLT2 is highly conserved between mice and human with 93% identity, compared with 78% identity for BLT1, suggesting important but as yet undefined functions for BLT2. Whereas human and mouse BLT1 are expressed exclusively in leukocytes, human BLT2 is distributed more widely (32, 33). Membrane fractions of HEK293 cells transfected with human BLT2 exhibited LTB4 binding with a Kd of 22.7 nM, ~20-fold higher than that of BLT1 transfectants. BLT2 coupled to both the Gi and Gq family of G-proteins as did BLT1, and CHO cells expressing BLT2 exhibited LTB4-induced increases in intracellular calcium and chemotactic responses. BLT2 binds various hydroxyeicosatetraenoic acids in addition to LTB4 (36). Murine BLT2 has been characterized and is highly expressed in keratinocytes (47). The biological roles of BLT2 have not been reported. However, the analysis of BLT2 is expected to reveal novel functions of LTB4 and structurally related eicosanoids.


   Biochemical Characterization of BLT1: Roles of Helix 8
TOP
 ABSTRACT
 INTRODUCTION
 Discovery and Signaling of...
 Physiological Roles of BLT1
 Discovery and Signaling of...
 Biochemical Characterization of...
Conclusion
 REFERENCES
 
GPCRs form a large superfamily of seven-transmembrane helix proteins that mediate responses to various ligands. Some examples are shown in Fig. 1. Although the first and sole high resolution structure of a GPCR, rhodopsin (37), is very helpful in understanding the intramolecular mechanism of GPCR activation, the mechanisms of receptor activation and inactivation remain unclear. In response to extracellular ligands, GPCRs undergo conformational changes, promote the exchange of GDP for GTP on the G-protein {alpha} subunit, and initiate the dissociation of the {alpha}- and {beta}{gamma}-subunits. After G-protein activation, GPCRs are inactivated by several mechanisms. The best characterized mechanism of inactivation involves phosphorylation of cytoplasmic Ser/Thr residues of GPCRs by GPCR kinase, protein kinase C, and cAMP-dependent protein kinase, which leads to {beta}-arrestin-dependent internalization of GPCRs (38). GPCRs are also known to switch into a low affinity state following exposure to ligands. This is caused by GDP-GTP exchange on the {alpha} subunit of heterotrimeric G-proteins, because addition of GTP{gamma}S (a nonhydrolyzable GTP analogue) to membrane preparations induces a structural change of GPCR into a low affinity state.



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  		FIGURE 1.
Phylogenetic tree of putative lipid GPCRs including BLT1 and BLT2. Lysophospholipid receptors are shown in yellow, fatty acid-derived ligands in blue, proton-sensing receptors in red, and other GPCRs (mainly orphan) in white. This tree was constructed using "All All Program" at The Computational Biochemistry Server at ETHZ (cbrg.inf.ethz.ch/ServerBooklet/chapter2_3.html).

 
Given that BLT1 is a very specific GPCR for LTB4 and is not expressed in cultured cell lines commonly used for GPCR transfection, BLT1 is a unique tool for analyzing the molecular mechanism of activation and inactivation of GPCRs in vitro. BLT1 is expressed and sorted to the plasma membrane in most cells after transfection, and examination of [3H]LTB4 binding by overexpressed BLT1 is straightforward because of its low nonspecific binding. Baneres and Parello (39, 40) have reported that only one G-protein trimer binds to a dimerized receptor to form a pentameric complex using BLT1 protein expressed in Escherichia coli. Analysis of the crystal structure of rhodopsin confirmed the presence of 7 transmembrane (TM) helices and revealed the existence of an 8th helix (helix 8) that projects at a right angle from the C terminus of TM7 (37) (Fig. 2). This short helix of rhodopsin is anchored by a palmitoyl group to the cytoplasmic leaflet of the cell membrane, and a hypothetical model has predicted that helix 8 interacts with the N-terminal helix of the G{alpha} and G{gamma} subunits (41). BLT1 belongs to the rhodopsin subfamily of GPCRs and is speculated to contain the helix 8 in its intracellular C terminus (42, 43). However, BLT1 lacks the cysteine residue, which is thought to be palmitoylated in many GPCRs. BLT1 showed little internalization following exposure to LTB4 in HEK293 or CHO cells, in contrast to the robust internalization of the PAF receptor (42, 44).

BLT1 mutants with a truncated or substituted helix 8 showed much higher LTB4 binding than wild-type (WT) receptor in HEK293 and CHO cells, albeit with comparable expression on the cell surface (42). Similar to the WT receptor, LTB4 promoted GTP{gamma}S binding in these mutants following exposure to LTB4. Unlike WT-BLT1, the addition of GTP{gamma}S did not inhibit LTB4 binding to the mutant receptors. The mutant receptors maintained a high affinity for LTB4, even in the presence of an excess amount of GTP{gamma}S, as determined by Scatchard analyses. Consistent with this observation, the mutant receptors showed more prolonged intracellular signaling (e.g. calcium mobilization and metabolic activation) after LTB4 treatment. Fig. 3 is a molecular model of BLT1 (based on the rhodopsin structure as a reference) and shows a close-up of the residues in the vicinity of helix 8. The BLT1 model predicts a helix 8 extending from TM7 similar to the one observed in rhodopsin. The BLT1 model suggests that a pair of aromatic residues (Tyr-285 and Phe-300), which are positioned similarly to the conserved Tyr-306 and Phe-313 pair in rhodopsin, may stabilize the inactive form of the receptor by holding TM7 and helix 8 at almost a right angle to each other. Hydrophobic amino acid residues (Val-301, Leu-304, and Leu-305) of the short helix 8 may anchor this helix to the plasma membrane like palmitoylated cysteine. A phosphorylation site (Thr-308) is located just after the amphiphilic helix 8, and phosphorylation of Thr-308 is predicted to weaken the interaction between helix 8 and the plasma membrane. Gaudreau et al. (45) proposed that Thr-308 is involved in GRK6-mediated desensitization of BLT1 signaling. Phosphorylation at that site may also play a role in inactivation of BLT1. Gaudreau et al. (43) also proposed that helix 8 is involved in a hydrophobic core containing other hydrophobic residues in helix 1. Disruption of this hydrophobic core may facilitate the irreversible activation of BLT1. Cell surface expression levels of helix 8 mutants of BLT2 are considerably reduced.3 The helix 8 of BLT2 might also be important for receptor sorting.



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  		FIGURE 2.
Characteristic amino acid residues of helix 8 of rhodopsin family GPCRs. Alignments of helix 8 of 180 human rhodopsin family GPCRs are summarized using GPCRDB (www.gpcr.org/7tm). The numbers of amino acid residues from Tyr-306 of the NPXXY sequence to Phe-313 of the N terminus of helix 8 are 6 (163 receptors), 5 (7 amine receptors), 7 (8 prostanoid receptors), or 14 (2 BLTs). The most and second most frequent amino acids are shown with the corresponding amino acids of bovine rhodopsin, and the frequency is shown in parentheses. Hydrophobic amino acids are Ala, Phe, Ile, Leu, Met, Pro, Val, Trp; hydrophilic amino acids are Cys, Gly, Asn, Gln, Ser, Thr, Tyr; basic amino acids are His, Lys, Arg; acidic amino acids are Asp, Glu. H, hydrophobic; A, aromatic; P, possibly palmitoylated; B, basic amino acids.

 



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  		FIGURE 3.
BLT1 structure model. A, the BLT1 atomic model is based on that of bovine rhodopsin (Protein Data Bank entry 1F88 [PDB] ) with homology modeling as a rhodopsin subfamily member of GPCRs. Helix 8 with side chains in a stick model is shown. The vicinity of helix 8 is presented in the color green, helix 8 is in violet, transmembrane helix 7 is in pink, and helix 1isin blue. In helix 8, the hydrophobic side chains of Val-301, Leu-304, and Leu-305 are colored in violet and extrude to the plasma membrane, and a pair of aromatic residues, Tyr-285 and Phe-300, with the transparent Corey-Pauling-Koltun surface may restrain helices 7 and 8. B, Edmundson helical wheel projection of helix 8. The hydrophobic and hydrophilic amino acids cluster on opposite sides.

 



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  		FIGURE 4.
A model depicting functions of BLT1 helix 8. Although wild-type BLT1 can change its conformation from a high affinity state to a low affinity state after G-protein activation (A), the BLT1 mutant that lacks helix 8 cannot change its conformation to the low affinity state (B). The helix 8 of BLT1 may function in sensing the status of its coupling G{alpha} subunit as being GTP-bound or being anchored in the plasma membrane; as a consequence the receptor may change its conformation. Therefore, helix 8 mutants may remain in a high affinity state and exhibit higher LTB4 binding and more prolonged intracellular signaling (42).

 
Although one will have to wait for the three-dimensional structure of the BLT1-G-protein complex, these studies suggest that helix 8 of BLT1 may play an important role in the inactivation of BLT1 after G-protein activation, possibly by sensing G{alpha} subunits as being GTP-bound (Fig. 4). Using reconstitution of a budded baculovirus expression system, Masuda et al. (46) showed that trimeric G-proteins were required for maintenance of the high affinity state of BLT1. The binding affinity of GPCR is critically dependent on the status of G-proteins, and biochemical studies of GPCRs are important in understanding the molecular mechanisms of receptor activation and inactivation.


   Conclusion
TOP
 ABSTRACT
 INTRODUCTION
 Discovery and Signaling of...
 Physiological Roles of BLT1
 Discovery and Signaling of...
 Biochemical Characterization of...
 Conclusion
REFERENCES
 
In addition to the physiological and pathophysiological importance of BLT1 as revealed by analyses of BLT1-deficient mice, BLT1 is a useful molecular device for analyzing the mechanism of activation and inactivation of GPCRs in vitro. The C terminus of BLT1 plays an important role in sensing GDP and GTP on the G-protein {alpha} subunit to which BLT1 couples and in switching the affinity states of BLT1 for LTB4. It will be important to know whether this sensing mechanism (via the 8 helix) is common to the other GPCRs or only limited to a small population of GPCRs, including BLT1.


   FOOTNOTES
 
* This minireview will be reprinted in the 2005 Minireview Compendium, which will be available in January, 2006. Back

1 To whom correspondence should be addressed. Tel.: 81-3-5841-3499; Fax: 81-3-5841-3405; E-mail: t-okuno{at}umin.ac.jp.

2 The abbreviations used are: LT, leukotriene; GPCR, G-protein-coupled receptor; PAF, platelet-activating factor; HEK, human embryonic kidney; CHO, Chinese hamster ovary; PTX, pertussis toxin; GTP{gamma}S, guanosine 5'-O-(3-thio)triphosphate; TM, transmembrane; WT, wild-type. Back

3 T. Okuno, T. Yokomizo, and T. Shimizu, unpublished data. Back



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TOP
 ABSTRACT
 INTRODUCTION
 Discovery and Signaling of...
 Physiological Roles of BLT1
 Discovery and Signaling of...
 Biochemical Characterization of...
 Conclusion
 REFERENCES
 

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